Ubiquitination is a post-translational modification of proteins that regulate a host of important cellular processes including degradation of cellular proteins, expression of genes, and protein/membrane trafficking. Ubiquitination of proteins and the specificity of ubiquitination are mediated by three classes of ubiquitin ligases (E1, E2, and E3). In addition to the ligases, a variety of deubiquitinating enzymes (DUBs) may regulate ubiquitination in cells. DUBs include ubiquitin carboxy-terminal hydrolase L1 (Uch-L1), a protein selectively expressed in neurons and in sertoli cells of testis. Defects in Ubiquitination/proteasomal mechanisms are implicated in the pathogenesis of many neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. In particular, pathogenic relationship between defects in ubiquitin/proteasomal pathway and degeneration of dopaminergic neurons are indicated by the fact that PD-associated mutations are identified in Parkin, an E3-ubiquitin ligase, and Uch-L1. In gad mutant mice, deletion of exon 7 and 8 of Uch-L1 gene leads to degeneration of neurons in the DRG and in the gracile nucleus and early lethality. However, because Uch-L1 is expressed at high levels in many neuronal populations, Uch-L1 function may be important in other neurons. Because of early lethality and general underlying movement defect in gad mice, the functional importance of Uch-L1 in a various neuronal population and as a function of aging can not be examined effectively. We propose generate a mice where the expression of Uch-L1 can be temporally and spatially regulated. Specifically, we will generate UchL1-floxed mice to conditionally silence Uch-L1 expression by mating to appropriate Cre expressing mice. As an initial test of our hypothesis, we will determine whether Uch-L1 activity is important for normal functioning and aging of the dopaminergic and noradrenergic neurons by mating. The IoxP-targeted Uch1 mice will be mated to pTH-Cre transgenic mice to silence Uch-L1 expression only in the dopaminergic and noradrenergic neurons.